Regulation of physiology and behaviour through G-protein coupled receptors of the nervous system

通过神经系统 G 蛋白偶联受体调节生理和行为

• 批准号: RGPIN-2018-05245
• 负责人: Bendena, William
• 金额: $ 2.4万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684975
• 关键词: Regulation; physiology; behaviour; through; protein

The nervous system is a complex network of nerve cells that create a circuit that perceives sensory information and creates a response. Failure of one or more proteins in a nerve cell within this circuit may disrupt the normal nerve transmission circuit. Disruption of neural circuits have been implicated in a variety of human diseases including schizophrenia, epilepsy, autism spectrum disorder, attention-deficit hyperactivity disorder, post-traumatic stress disorder and depression. Human nerve cells are complex in their number and the number of connections they can make with other nerve cells. As such we have chosen to work with the model organism Caenorhabditis elegans, a nematode worm with a simple nervous system of only 302 nerve cells. Sensory neurons detect the environment and pass that information through neural connections to interneurons that interpret the signal and pass the information to motor neurons to create a response. In our model, a neuropeptide receptor NPR-9 is expressed in only one C. elegans interneuron. A mutation in gene npr-9 creates an animal with limited movement or foraging behaviour when it is placed on food. npr-9 mutant animals eat the same amount of food as normal animals but gain excessive fat. This suggests that a component of the nervous system is regulating fat metabolism. We have found that when NPR-9 receptor is over-expressed, the animal becomes a hyper-roamer and is unable to sense where to find food. ******We are using genetic and molecular techniques to understand the signaling molecules controlling NPR-9 function and learn how NPR-9 works with classical neurotransmitters and other molecules to transmit a nerve signal and create the normal behaviourial response. We are particularly interested in discovering novel proteins that function in circuit interpretation. As many of the proteins in the nervous system of C. elegans have counterparts in human systems, this research will uncover proteins that can be tested as essential for complex neural signaling and nerve cell contributions to metabolic change. ******A second outcome of this research is that over-activation of NPR-9 leads to an animal that doesn't feed, because it lacks the sensory cues to identify food. This finding provides an opportunity to test chemical compounds (analogues) that may over-stimulate NPR-9 equivalent proteins in disease causing parasitic nematode species and thus cause them to stop feeding and die (an anthelmintic) without harming the host. ******This work will also train at least 2-3 graduate students and 3-4 undergraduate students annually in classical genetics, modern molecular biology applications such as RNAseq and bioinformatics and mammalian expression assays. These are techniques that have wide applicability to numerous scientific disciplines.

神经系统是一个复杂的神经细胞网络，它创造了一个感知感官信息并产生反应的回路。在该回路内的神经细胞中的一种或多种蛋白质的失效可能会破坏正常的神经传递回路。神经回路的中断与各种人类疾病有关，包括精神分裂症、癫痫、自闭症谱系障碍、注意力缺陷多动障碍、创伤后应激障碍和抑郁症。人类神经细胞的数量和它们与其他神经细胞的连接数量是复杂的。因此，我们选择了模式生物秀丽隐杆线虫（Caushabditis elegans），一种只有302个神经细胞的简单神经系统的线虫。感觉神经元检测环境并通过神经连接将信息传递给中间神经元，中间神经元解释信号并将信息传递给运动神经元以产生反应。在我们的模型中，神经肽受体NPR-9仅在一个C中表达。中间神经元 基因npr-9的一个突变使动物在进食时运动或觅食行为受到限制。npr-9突变动物吃的食物量与正常动物相同，但脂肪过多。这表明神经系统的一个组成部分正在调节脂肪代谢。我们已经发现，当NPR-9受体过度表达时，动物会变得过度漫游，无法感知到哪里可以找到食物。 ****** 我们正在使用遗传和分子技术来了解控制NPR-9功能的信号分子，并了解NPR-9如何与经典神经递质和其他分子一起传递神经信号并产生正常的行为反应。我们特别感兴趣的是发现在电路解释中起作用的新蛋白质。由于C.虽然线虫在人类系统中有对应的蛋白质，但这项研究将发现可以被测试为复杂神经信号和神经细胞对代谢变化的贡献所必需的蛋白质。** 这项研究的第二个结果是，NPR-9的过度激活导致动物不进食，因为它缺乏识别食物的感官线索。这一发现提供了一个机会来测试化学化合物（类似物），这些化合物可能过度刺激致病寄生线虫物种中的NPR-9等效蛋白，从而导致它们停止进食并死亡（驱虫剂）而不伤害宿主。 ** 这项工作还将每年培训至少2-3名研究生和3-4名本科生，涉及经典遗传学、现代分子生物学应用（如RNAseq和生物信息学）以及哺乳动物表达测定。这些技术对许多科学学科具有广泛的适用性。